Advertisement

Expression of Macrophage Antigens by Tumor Cells

  • Ivan Shabo
  • Joar SvanvikEmail author
Chapter
  • 1.9k Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 950)

Abstract

Macrophages are a heterogeneous cell population of the myeloid linage derived from monocytes. These cells show two different polarization states, M1 and M2 macrophages in response to different micro environmental signals. Tumor associated macrophages (TAM) represent the M2 type and promote tumor progression. These cells express antigens that more or less are specific for macrophages like: CD14, CD68, MAC387, CD163, and DAP12. In a series of recent studies it is shown that cancer cells may express these antigens and CD163, MAC387 and DAP12 may be expressed by e.g. breast cancer cells. Thus, 48% of the breast cancers expressed CD163 that is a scavenger receptor normally expressed by macrophages alone. The corresponding figure for rectal cancer is 31%. The expression of CD163 is correlated to early distant recurrence in breast cancer and local recurrence in rectal cancer and reduced survival time in both conditions. Expression of macrophage antigens in breast- and colorectal-cancers may have a prognostic relevance in clinical praxis. One explanation to these findings is that resemblance with macrophages may indicate a more invasive phenotype due to genetic exchange between the primary tumor cells and associated macrophages. This is further supported by the finding that expression of DAP12, a macrophage fusion receptor, in breast cancer is associated with an advanced tumor grade and higher rates of skeletal and liver metastases and overall shorter distant recurrence free survival. Another explanation to the changed phenotype is a genetic exchange between the cells by exosome-mediated transfer.

Keywords

Rectal Cancer CD163 Expression Cell Fusion Multinucleated Giant Cell CD163 Positive Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Mantovani A, Bottazzi B, Colotta F et al (1992) The origin and function of tumor-associated macrophages. Immunol Today 13:265–270PubMedCrossRefGoogle Scholar
  2. 2.
    Mantovani A, Schioppa T, Biswas SK et al (2003) Tumor-associated macrophages and dendritic cells as prototypic type II polarized myeloid populations. Tumori 89:459–468PubMedGoogle Scholar
  3. 3.
    Mantovani A, Schioppa T, Porta C et al (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25:315–322PubMedCrossRefGoogle Scholar
  4. 4.
    Mantovani A, Sozzani S, Locati M et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555PubMedCrossRefGoogle Scholar
  5. 5.
    Martinez FO, Sica A, Mantovani A et al (2008) Macrophage activation and polarization. Front Biosci 13:453–461PubMedCrossRefGoogle Scholar
  6. 6.
    Vignery A (2005) Macrophage fusion: the making of osteoclasts and giant cells. J Exp Med 202:337–340PubMedCrossRefGoogle Scholar
  7. 7.
    Larizza L, Schirrmacher V, Graf L et al (1984) Suggestive evidence that the highly metastatic variant ESb of the T-cell lymphoma eb is derived from spontaneous fusion with a host macrophage. Int J Cancer 34:699–707PubMedCrossRefGoogle Scholar
  8. 8.
    Larizza L, Schirrmacher V, Pfluger E (1984) Acquisition of high metastatic capacity after in vitro fusion of a nonmetastatic tumor line with a bone marrow-derived macrophage. J Exp Med 160:1579–1584PubMedCrossRefGoogle Scholar
  9. 9.
    Munzarova M, Lauerova L, Capkova J (1992) Are advanced malignant melanoma cells hybrids between melanocytes and macrophages? Melanoma Res 2:127–129PubMedCrossRefGoogle Scholar
  10. 10.
    Munzarova M, Lauerova L, Kovarik J et al (1992) Fusion-induced malignancy? A preliminary study. (A challenge to today’s common wisdom). Neoplasma 39:79–86PubMedGoogle Scholar
  11. 11.
    Munzarova M, Zemanova D (1992) Transformation of blood monocytes to multinucleated giant cells in vitro: are there any differences between malignant and nonmalignant states? Physiol Res 41:221–226PubMedGoogle Scholar
  12. 12.
    Busund LT, Killie MK, Bartnes K et al (2002) Spontaneously formed tumorigenic hybrids of meth A sarcoma and macrophages grow faster and are better vascularized than the parental tumor. Int J Cancer 100:407–413PubMedCrossRefGoogle Scholar
  13. 13.
    Pawelek JM, Chakraborty AK, Rachkovsky ML et al (1999) Altered N-glycosylation in macrophage x melanoma fusion hybrids. Cell Mol Biol (Noisy-Le-Grand) 45:1011–1027Google Scholar
  14. 14.
    Pawelek JM (2000) Tumour cell hybridization and metastasis revisited. Melanoma Res 10:507–514PubMedCrossRefGoogle Scholar
  15. 15.
    Chakraborty AK, Sodi S, Rachkovsky M et al (2000) A spontaneous murine melanoma lung metastasis comprised of host x tumor hybrids. Cancer Res 60:2512–2519PubMedGoogle Scholar
  16. 16.
    Chakraborty AK, Pawelek J, Ikeda Y et al (2001) Fusion hybrids with macrophage and melanoma cells up-regulate N-acetylglucosaminyltransferase V, beta1-6 branching, and metastasis. Cell Growth Differ 12:623–630PubMedGoogle Scholar
  17. 17.
    Chakraborty AK, de Freitas Sousa J, Espreafico EM et al (2001) Human monocyte x mouse melanoma fusion hybrids express human gene. Gene 275:103–106PubMedCrossRefGoogle Scholar
  18. 18.
    Nygren JM, Jovinge S, Breitbach M et al (2004) Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 10:494–501PubMedCrossRefGoogle Scholar
  19. 19.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM et al (2003) Fusion of bone-marrow-derived cells with purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973PubMedCrossRefGoogle Scholar
  20. 20.
    Mortensen K, Lichtenberg J, Thomsen PD et al (2004) Spontaneous fusion between cancer cells and endothelial cells. Cell Mol Life Sci 61:2125–2131PubMedCrossRefGoogle Scholar
  21. 21.
    Terada N, Hamazaki T, Oka M et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedCrossRefGoogle Scholar
  22. 22.
    Johansson CB, Youssef S, Koleckar K et al (2008) Extensive fusion of haematopoietic cells with purkinje neurons in response to chronic inflammation. Nat Cell Biol 10:575–583PubMedCrossRefGoogle Scholar
  23. 23.
    Pawelek JM, Chakraborty AK (2008) Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8:377–386PubMedCrossRefGoogle Scholar
  24. 24.
    Shabo I, Olsson H, Sun XF et al (2009) Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer 125:1826–1831PubMedCrossRefGoogle Scholar
  25. 25.
    Shabo I, Stal O, Olsson H et al (2008) Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer 123:780–786PubMedCrossRefGoogle Scholar
  26. 26.
    Ziegler-Heitbrock HW, Ulevitch RJ (1993) CD14: cell surface receptor and differentiation marker. Immunol Today 14:121–125PubMedCrossRefGoogle Scholar
  27. 27.
    Bazil V, Baudys M, Hilgert I et al (1989) Structural relationship between the soluble and membrane-bound forms of human monocyte surface glycoprotein CD14. Mol Immunol 26:657–662PubMedCrossRefGoogle Scholar
  28. 28.
    Kirkland TN, Viriyakosol S (1998) Structure-function analysis of soluble and membrane-bound CD14. Prog Clin Biol Res 397:79–87PubMedGoogle Scholar
  29. 29.
    Viriyakosol S, Mathison JC, Tobias PS et al (2000) Structure-function analysis of CD14 as a soluble receptor for lipopolysaccharide. J Biol Chem 275:3144–3149PubMedCrossRefGoogle Scholar
  30. 30.
    Peterson PK, Gekker G, Hu S et al (1995) CD14 receptor-mediated uptake of nonopsonized mycobacterium tuberculosis by human microglia. Infect Immun 63:1598–1602PubMedGoogle Scholar
  31. 31.
    Tamai R, Sakuta T, Matsushita K et al (2002) Human gingival CD14(+) fibroblasts primed with gamma interferon increase production of interleukin-8 in response to lipopolysaccharide through up-regulation of membrane CD14 and MyD88 mRNA expression. Infect Immun 70:1272–1278PubMedCrossRefGoogle Scholar
  32. 32.
    Frey EA, Miller DS, Jahr TG et al (1992) Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med 176:1665–1671PubMedCrossRefGoogle Scholar
  33. 33.
    Pugin J, Ulevitch RJ, Tobias PS (1993) A critical role for monocytes and CD14 in endotoxin-induced endothelial cell activation. J Exp Med 178:2193–2200PubMedCrossRefGoogle Scholar
  34. 34.
    Saito N, Pulford KA, Breton-Gorius J et al (1991) Ultrastructural localization of the CD68 macrophage-associated antigen in human blood neutrophils and monocytes. Am J Pathol 139:1053–1059PubMedGoogle Scholar
  35. 35.
    Holness CL, da Silva RP, Fawcett J et al (1993) Macrosialin, a mouse macrophage-restricted glycoprotein, is a member of the lamp/lgp family. J Biol Chem 268:9661–9666PubMedGoogle Scholar
  36. 36.
    Holness CL, Simmons DL (1993) Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:1607–1613PubMedGoogle Scholar
  37. 37.
    Kurushima H, Ramprasad M, Kondratenko N et al (2000) Surface expression and rapid internalization of macrosialin (mouse CD68) on elicited mouse peritoneal macrophages. J Leukoc Biol 67:104–108PubMedGoogle Scholar
  38. 38.
    Ramprasad MP, Terpstra V, Kondratenko N et al (1996) Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein. Proc Natl Acad Sci USA 93:14833–14838PubMedCrossRefGoogle Scholar
  39. 39.
    Khazen W, M’Bika J-P, Tomkiewicz C et al (2005) Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Letters 579:5631–5634PubMedGoogle Scholar
  40. 40.
    Kunisch E, Fuhrmann R, Roth A et al (2004) Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis 63:774–784PubMedCrossRefGoogle Scholar
  41. 41.
    Doussis IA, Gatter KC, Mason DY (1993) CD68 reactivity of non-macrophage derived tumours in cytological specimens. J Clin Pathol 46:334–336PubMedCrossRefGoogle Scholar
  42. 42.
    Gloghini A, Rizzo A, Zanette I et al (1995) KP1/CD68 expression in malignant neoplasms including lymphomas, sarcomas, and carcinomas. Am J Clin Pathol 103:425–431PubMedGoogle Scholar
  43. 43.
    Facchetti F, Bertalot G, Grigolato PG (1991) KP1 (CD 68) staining of malignant melanomas. Histopathology 19:141–145PubMedCrossRefGoogle Scholar
  44. 44.
    Cassidy M, Loftus B, Whelan A et al (1994) KP-1: not a specific marker. Staining of 137 sarcomas, 48 lymphomas, 28 carcinomas, 7 malignant melanomas and 8 cystosarcoma phyllodes. Virchows Arch 424:635–640PubMedCrossRefGoogle Scholar
  45. 45.
    Strojnik T, Kavalar R, Zajc I et al (2009) Prognostic impact of CD68 and kallikrein 6 in human glioma. Anticancer Res 29:3269–3279PubMedGoogle Scholar
  46. 46.
    Ribé A, McNutt NS (2003) S100A protein expression in the distinction between lentigo maligna and pigmented actinic keratosis. Am J Dermatopathol 25:93–99PubMedCrossRefGoogle Scholar
  47. 47.
    Loftus B, Loh LC, Curran B et al (1991) Mac387: its non-specificity as a tumour marker or marker of histiocytes. Histopathology 19:251–255PubMedCrossRefGoogle Scholar
  48. 48.
    Lopez-Beltran A, Requena MJ, Alvarez-Kindelan J et al (2007) Squamous differentiation in primary urothelial carcinoma of the urinary tract as seen by MAC387 immunohistochemistry. J Clin Pathol 60:332–335PubMedCrossRefGoogle Scholar
  49. 49.
    Fabriek BO, Dijkstra CD, van den Berg TK (2005) The macrophage scavenger receptor CD163. Immunobiology 210:153–160PubMedCrossRefGoogle Scholar
  50. 50.
    Kristiansen M, Graversen JH, Jacobsen C et al (2001) Identification of the haemoglobin scavenger receptor. Nature 409:198–201PubMedCrossRefGoogle Scholar
  51. 51.
    Nguyen TT, Schwartz EJ, West RB et al (2005) Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage. Am J Surg Pathol 29:617–624PubMedCrossRefGoogle Scholar
  52. 52.
    Stover CM, Schleypen J, Gronlund J et al (2000) Assignment of CD163B, the gene encoding M160, a novel scavenger receptor, to human chromosome 12p13.3 By in situ hybridization and somatic cell hybrid analysis. Cytogenet Cell Genet 90:246–247PubMedCrossRefGoogle Scholar
  53. 53.
    Pioli PA, Goonan KE, Wardwell K et al (2004) TGF-beta regulation of human macrophage scavenger receptor CD163 is smad3-dependent. J Leukoc Biol 76:500–508PubMedCrossRefGoogle Scholar
  54. 54.
    Ritter M, Buechler C, Langmann T et al (1999) The scavenger receptor CD163: regulation, promoter structure and genomic organization. Pathobiology 67:257–261PubMedCrossRefGoogle Scholar
  55. 55.
    Sulahian TH, Hogger P, Wahner AE et al (2000) Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 12:1312–1321PubMedCrossRefGoogle Scholar
  56. 56.
    Komohara Y, Hirahara J, Horikawa T et al (2006) AM-3 k, an anti-macrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype. J Histochem Cytochem 54:763–771PubMedCrossRefGoogle Scholar
  57. 57.
    Sica A, Schioppa T, Mantovani A et al (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727PubMedCrossRefGoogle Scholar
  58. 58.
    Shabo I, Olsson H, Sun XF et al (2009) Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer 125:1826–1831Google Scholar
  59. 59.
    Swedish Rectal Cancer Trial (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980–987CrossRefGoogle Scholar
  60. 60.
    Jensen TO, Schmidt H, Steiniche T et al (2010) Melanoma cell expression of macrophage markers in AJCC stage I/II melanoma. J Clin Oncol (Meeting Abstracts) 28:e19034–Google Scholar
  61. 61.
    Kaifu T, Nakahara J, Inui M et al (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332PubMedGoogle Scholar
  62. 62.
    Paloneva J, Mandelin J, Kiialainen A et al (2003) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198:669–675PubMedCrossRefGoogle Scholar
  63. 63.
    Lucas M, Daniel L, Tomasello E et al (2002) Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice. Eur J Immunol 32:2653–2663PubMedCrossRefGoogle Scholar
  64. 64.
    Ivashkiv LB (2009) Cross-regulation of signaling by ITAM-associated receptors. Nat Immunol 10:340–347PubMedCrossRefGoogle Scholar
  65. 65.
    Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306:1517–1519PubMedCrossRefGoogle Scholar
  66. 66.
    Bakker AB, Hoek RM, Cerwenka A et al (2000) DAP12-deficient mice fail to develop autoimmunity Due To impaired antigen priming. Immunity 13:345–353PubMedCrossRefGoogle Scholar
  67. 67.
    Valadi H, Ekstrom K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of SurgeryLinköping UniversityLinköpingSweden
  2. 2.Transplantation Center, Sahlgrenska University HospitalGothenburgSweden

Personalised recommendations